Target Information
| Target General Information | Top | |||||
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| Target ID |
T16308
(Former ID: TTDR00355)
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| Target Name |
Rotamase Pin1 (PIN1)
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| Synonyms |
Prolyl isomerase Pin1; Peptidyl-prolyl cis-trans isomerase Pin1; Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; Peptidyl prolyl cis/trans isomerase Pin1; PPIase Pin1
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| Gene Name |
PIN1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| Function |
By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes (, Ref. 21). Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation. Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner. Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN. May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR). Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs.
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| BioChemical Class |
Cis-trans-isomerase
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| UniProt ID | ||||||
| EC Number |
EC 5.2.1.8
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| Sequence |
MADEEKLPPGWEKRMSRSSGRVYYFNHITNASQWERPSGNSSSGGKNGQGEPARVRCSHL
LVKHSQSRRPSSWRQEKITRTKEEALELINGYIQKIKSGEEDFESLASQFSDCSSAKARG DLGAFSRGQMQKPFEDASFALRTGEMSGPVFTDSGIHIILRTE Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T20OEM | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Avastin+/-Tarceva | Drug Info | Phase 3 | Non-small-cell lung cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | Avastin+/-Tarceva | Drug Info | [1] | |||
| 2 | (R)-2-(2-naphthamido)-3-m-tolylpropanoic acid | Drug Info | [3] | |||
| 3 | (R)-2-(2-naphthamido)-3-p-tolylpropanoic acid | Drug Info | [3] | |||
| 4 | (R)-2-(2-naphthamido)-5-phenylpent-4-ynoic acid | Drug Info | [3] | |||
| 5 | (R)-3-(2-naphthamido)-4-m-tolylbutanoic acid | Drug Info | [3] | |||
| 6 | (R,)-2-(2-naphthamido)-5-phenylpent-4-enoic acid | Drug Info | [3] | |||
| 7 | 3,6,9,12,15,18-HEXAOXAICOSANE | Drug Info | [4] | |||
| 8 | Ac-Bth-Thr(PO3H2)-Pip-Nal-Gln-NH2 | Drug Info | [5] | |||
| 9 | Ac-Phe-D-Thr(PO3H2)-Pip-Nal-Gln-NH2 | Drug Info | [5] | |||
| 10 | Ac-Phe-Thr(PO3H2)-Pip-Nal-Gln-NH2 | Drug Info | [5] | |||
| 11 | Beta-(2-Naphthyl)-Alanine | Drug Info | [4] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: L-alanine | Ligand Info | |||||
| Structure Description | PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE FROM HOMO SAPIENS | PDB:1PIN | ||||
| Method | X-ray diffraction | Resolution | 1.35 Å | Mutation | No | [6] |
| PDB Sequence |
KLPPGWEKRM
15 SRSSGRVYYF25 NHITNASQWE35 RPSGGKNGQG50 EPARVRCSHL60 LVKHSQSRRP 70 SSWRQEKITR80 TKEEALELIN90 GYIQKIKSGE100 EDFESLASQF110 SDCSSAKARG 120 DLGAFSRGQM130 QKPFEDASFA140 LRTGEMSGPV150 FTDSGIHIIL160 RTE |
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| Ligand Name: Tretinoin | Ligand Info | |||||
| Structure Description | Structure of Pin1 PPIase domain bound with all-trans retinoic acid | PDB:4TNS | ||||
| Method | X-ray diffraction | Resolution | 1.33 Å | Mutation | Yes | [7] |
| PDB Sequence |
EPARVRCSHL
60 LVKHSQSRRP70 SSWRQEQITR80 TQEEALELIN90 GYIQKIKSGE100 EDFESLASQF 110 SDCSSAKARG120 DLGAFSRGQM130 QKPFEDASFA140 LRTGEMSGPV150 FTDSGIHIIL 160 RTE
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4) | 43.243 (32/74) | 2.74E-10 |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Viral life cycle - HIV-1 | hsa03250 | Affiliated Target |
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| Class: Genetic Information Processing => Information processing in viruses | Pathway Hierarchy | ||
| RIG-I-like receptor signaling pathway | hsa04622 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 1.23E-04 |
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| Closeness centrality | 2.43E-01 | Radiality | 1.43E+01 | Clustering coefficient | 3.21E-01 |
| Neighborhood connectivity | 8.69E+01 | Topological coefficient | 1.54E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | RIG-I-like receptor signaling pathway | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | p73 transcription factor network | |||||
| 2 | C-MYC pathway | |||||
| 3 | PDGFR-beta signaling pathway | |||||
| 4 | p53 pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | ISG15 antiviral mechanism | |||||
| 2 | Negative regulators of RIG-I/MDA5 signaling | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | ISG15 antiviral mechanism | |||||
| 2 | RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Overexpression of PIN1 Enhances Cancer Growth and Aggressiveness with Cyclin D1 Induction in EBV-Associated Nasopharyngeal Carcinoma.PLoS One. 2016 Jun 3;11(6):e0156833. | |||||
| REF 2 | Clinical pipeline report, company report or official report of Roche. | |||||
| REF 3 | Structure-based design of novel human Pin1 inhibitors (II). Bioorg Med Chem Lett. 2010 Apr 1;20(7):2210-4. | |||||
| REF 4 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 5 | Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries. J Med Chem. 2006 Apr 6;49(7):2147-50. | |||||
| REF 6 | Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Cell. 1997 Jun 13;89(6):875-86. | |||||
| REF 7 | Structure of Pin1 PPIase domain bound with all-trans retinoic acid | |||||
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